The metabolic disease known as diabetes mellitus afflicts a large and growing number of people worldwide. In order to manage this health condition, frequent monitoring of blood glucose level is essential, especially for the patients who require regular insulin injections. To reduce risk of severe long-term health complications, it is recommended that diabetes patients check blood sugar level up to five times a day to maintain physiological glucose concentration between 90 and 120 mg/dl [A. C. Guyton and J. E. Hall, Textbook of medical physiology 10th ed. Philadelphia, Ch. 78 (2000)]. The standard technique for measurement of glucose concentration requires skin puncture to draw a small blood sample (typically microliter volume) which can be examined using a test strip and automated meter to report the results. Although this technique provides accurate glucose concentration data, frequent skin puncture is associated with significant discomfort, pain and risk of infection. Besides, it cannot be used for continuously monitoring glucose levels, an essential requirement especially for some categories of diabetics, including juvenile diabetes. Continuous monitoring also enables the creation of a real-time insulin pump—a much sought after mode of insulin delivery that better mimics the normal physiological condition. Over the past two decades, search for alternative methods of glucose monitoring resulted in development of a number of optical technologies including an IR absorption technique [H. Zeller, P. Novak and R. Landgraf, Int. J. Art. Org. 12, 129 (1989)], the pulsed photoacoustic method [H. A. MacKenzie, H. S. Ashton, S. Spiers, Y. Shen, S. S. Freeborn, J. Hannigan, J. Lindberg and P. Rae Clinical Chem. 45, 1587 (1999); K. M. Quan, G. B. Christison, H. A. MacKenzie and P. Hodgson, Phys. Med. Biol. 38, 1911 (1993)], polarimetry [G. L. Cote, M. D. Fox and R. B. Northrop, IEEE Trans. Biomed. Eng. 44, 1221 (1992)] and Raman spectroscopy [A. J. Berger, Y. Wang and M. S. Feld, Appi. Opt. 35, 209 (1996)].
Despite significant effort directed towards the development of non-invasive and minimally-invasive techniques for glucose monitoring [O, S. Khalil, Clinical Chem. 45, 165 (1999); G. L. Cote and R. J. McNichols, Biomedical Photonics Handbook, Ed.: Tuan Vo-Dinh, Ch. 18 (CRC Press) (2003)], no completely non-invasive sensor satisfying sensitivity and specificity conditions similar to intrusive sensors is available at the moment. [R. W. Waynant and V. M. Chenault (April 1998), “Overview of Non-Invasive Fluid Glucose Measurement Using Optical Techniques to Maintain Glucose Control in Diabetes Mellitus”, at http://www.ieee.org/organizations/pubs/newsletters/leos/apr98/overview.htm (LEOS Newsletter, Vol. 12)]. Traditionally, the near-IR spectral range (0.8-3 μm) has been explored for the development of optical technologies for glucose monitoring because of relatively low water absorption [M. Robinson, R. P. Eaton, D. M. Haaland, D. W. Koepp, E. V. Thomas, B. R. Stallard, and P. L. Robinson, Clin. Chem. 38, 1618 (1992); M. A. Arnold and G. W. Small, Anal. Chem. 62, 1457 (1990); D. Kajiwara, T. Uemura, H. Kishikawa, K. Nishida, Y. Hashiguchi, M. Uehara, M. Sakakida, K. Ilchinose and M. Shichiri, Med. Biol. Eng. Comput. 31, S17 (1993); R. Marbach, Th. Koschinsky, F. A. Gries and H. M. Heise, Appl. Spectrosc. 47, 875 (1993)]. Quantitative interpretation of spectroscopic data in the near-IR often requires sophisticated processing algorithms due to overlap of glucose molecule overtones and absorption bands of other tissue analytes. Farther into the mid-IR region (2.5-10 μm), the spectrum of anhydrous glucose has more than 20 absorption peaks, not all of which are specific to this molecule. Of particular significance, however, is the prominent absorption peak in the 8.5-10.5 μm band which is due to the carbon-oxygen-carbon bond in the pyrane ring of glucose. This feature is peaked at ca. 9.7 μm, and is isolated from other interfering peaks in human blood [C. J. Pouchert, The Aldrich Library of Infrared Spectra, 3 rd. ed., Aldrich Chemical Co. (1981)]. This peak is within the spectral range of the CO 2 laser which emits at several discrete wavelengths between 9.2 and 10.8 μm. A major difficulty for practical monitoring of glucose in human tissue within this spectral range is the intrinsic high-background absorption coefficient of water (640 cm−1 at 9.7 μm), which tends to fully dominate the relatively low normal concentration of glucose in human blood (typically 90 to 120 mg/dl). Nevertheless, a modulated CO 2 laser emission at 9.6 μm and a multiple attenuated total reflection (ATR) plate, both sides of which were immersed in the sample solution for signal enhancement (unrealistic for practical devices), was successfully used in obtaining definite correlations between ATR signal and glucose concentration in the range of 50-280 mg/dl [Y. Mendelson, C. Clermont, R. A. Peura and B-C. Lin, IEEE Trans. Biomed. Eng. 37, 458 (1990)]. Unfortunately, the data scatter in the critical 50 to 120 mg/dl range was on the order of 50-90% which is unacceptable for a practical device implementation. Several factors contributed to this: ATR plate heating, high signal sensitivity to the angle of incidence of the laser beam on the plate, the inherent depth inadequacy of the evanescent electromagnetic (EM) field probing only ca. 1.3 μm into the adjacent fluid zone, and the small, yet interfering, background absorptions (e.g. proteins) which cannot be eliminated using single-ended optical techniques. Besides, any practical implementation of this method would stumble on serious difficulties with regard to signal variations due to contact interface variations of the ATR prism from patient to patient and the presence of the glucose-deficient tissue surface epidermis layer (˜80 μm).